Novel thienothiophene compounds for long-acting injectable compositions and related methods

ABSTRACT

The present invention provides compounds useful for the treatment of opioid dependence, alcohol dependence, alcohol use disorder, or the prevention of relapse to opioid dependence in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication Ser. No. 62/697,899, filed on Jul. 13, 2018 and U.S.provisional patent application Ser. No. 62/699,290, filed on Jul. 17,2018. The entire teachings of the above applications are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to novel thienothiophene-containingcompounds and their use in long-acting injectable compositions. Inparticular, dimeric prodrugs of naltrexone are disclosed herein. Theinvention also relates to methods of use thereof.

BACKGROUND OF THE INVENTION

Opioid dependence and alcohol dependence are chronic disorders thatresult from a variety of genetic, psychological and environmentalfactors. Traditional treatment has consisted of two phases:detoxification and rehabilitation. Detoxification ameliorates thesymptoms and signs of withdrawal while rehabilitation helps the patientavoid future problems with opioids or alcohol. In the past, manyrehabilitative treatments have been psychosocial. More recently, therehas been increasing interest in medication-assisted treatment. Thesuccessful treatment of opioid dependence or alcohol dependence has manyserious challenges and complications. Patient compliance can be aparticularly difficult challenge to overcome. Accordingly, there is aneed for novel and improved therapies.

SUMMARY OF THE INVENTION

The compounds and methods described herein comprise one or more prodrugsof naltrexone. Upon administration, the compounds of the invention canbe converted in vivo to naltrexone. Following conversion, the activemoiety (i.e., naltrexone) is effective in treating subjects sufferingfrom opioid dependence or alcohol dependence or at risk of developingopioid dependence or alcohol dependence.

The invention provides prodrugs of naltrexone (NTX) having one or twomolecules of naltrexone covalently bound to a thienothiophene-containingmoiety. The compounds of the invention may extend the period duringwhich the naltrexone is released and absorbed after administration tothe subject, providing a longer duration of release than othercommercially available naltrexone products, such as VIVITROL®(naltrexone for extended-release injectable suspension) or REVIA®(naltrexone hydrochloride tablets USP).

Provided herein are compounds useful for the prevention or treatment ofopioid dependence or alcohol dependence in a subject in need thereof.

In an aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

is

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound with pointsof attachment selected from the 2 and 2′ positions or the 3 and 3′positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 2′positions, then the R groups are bound at the 3 and 3′ positions; or

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 3 and 3′positions, then the R groups are bound at the 2 and 2′ positions.

Examples of a compound of Formula I provided herein include a compoundof Formula Ia, Ib, Ic, or Id, or a pharmaceutically acceptable saltthereof.

In another aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein:

is

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound with points of attachment selected from the 2 and 2′positions or the 3 and 3′ positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 2′ positions, then the R groups are boundat the 3 and 3′ positions; or

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 3 and 3′ positions, then the R groups are boundat the 2 and 2′ positions.

Examples of a compound of Formula II provided herein include a compoundof Formula IIa, IIb, IIc, or IId, or a pharmaceutically acceptable saltthereof.

Also provided herein is a pharmaceutical composition comprising acompound of Formula I or II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

Also provided herein is a method of treating opioid dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of treating alcohol dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof.

Also provided herein is a method of preventing opioid dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of preventing relapse to opioiddependence in a subject in need thereof comprising administering to thesubject a compound of Formula I or II, or a pharmaceutically acceptablesalt thereof. In an embodiment, the opioid is an opioid agonist. In anembodiment, the opioid is morphine, fentanyl, oxymorphone,buprenorphine, hydromorphone, oxycodone, hydrocodone, diamorphine (i.e.,heroin) or the like. In another embodiment, the opioid is oxycodone ordiamorphine. In another embodiment, the opioid is buprenorphine.

Also provided herein is a method of preventing alcohol dependence in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof.

Also provided herein is a method of treating alcohol use disorder in asubject in need thereof comprising administering to the subject acompound of Formula I or II, or a pharmaceutically acceptable saltthereof. In another embodiment, the alcohol use disorder is moderate tosevere alcohol use disorder.

Also provided herein is a method for the blockade of the effects ofexogenously administered opioids in a subject in need thereof comprisingadministering to the subject a compound of Formula I or II, or apharmaceutically acceptable salt thereof. In an embodiment, the opioidis an opioid agonist. In an embodiment, the opioid is morphine,fentanyl, oxymorphone, buprenorphine, hydromorphone, oxycodone,hydrocodone, diamorphine (i.e., heroin) or the like. In anotherembodiment, the opioid is oxycodone or diamorphine. In anotherembodiment, the opioid is buprenorphine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the powder x-ray diffraction (PXRD) pattern for Compound 3.

DETAILED DESCRIPTION OF THE INVENTION

One of the challenges for delivering an active pharmaceutical ingredient(API) in a long-acting injectable composition is incorporating asufficient amount of drug to maintain effective plasma levels of APIover an extended period of time (e.g., several weeks or months) whilemaintaining a total composition volume that can be readily injected, ina single injection, into a subject. This challenge becomes still moredifficult when the API is in the form of a prodrug, and thus having amolecular weight higher than the parent API. Further, thephysicochemical properties of such a prodrug (including, but not limitedto, chemical stability, physical stability, physical form andsolubility) are important to its suitability for a long-actinginjectable composition.

Such long-acting injectable compositions can be in the form of asuspension of solids in an aqueous (liquid) composition. For example, asuspension of a prodrug of an API in an aqueous composition can beprepared for a long-acting composition. In such a system, thephysicochemical properties of the prodrug, including crystallinity andsolubility of the solid material, are important to its ability todeliver drug over an extended duration and with a therapeutic plasmaconcentration. In particular, crystalline prodrugs with low aqueoussolubility are important for long-acting injectable suspensions.

Provided herein are novel compounds which are prodrugs of naltrexone(NTX) having one or two covalently-attached naltrexone molecules,related methods of treating or preventing opioid dependence or alcoholdependence by administering one or more compounds of the invention,synthetic methods for making the compounds of the invention, andpharmaceutical compositions containing compounds of the invention.

In a non-limiting aspect, the compounds of the present invention mayundergo enzyme-mediated cleavage under physiological conditions torelease the naltrexone parent drug. In one embodiment, the ultimaterelease of the naltrexone parent drug is controlled by the rate ofdissolution of a crystalline compound of Formula I or II.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±10%, including ±5%, ±1%, and ±0.1%from the specified value, as such variations are appropriate to performthe disclosed methods.

As used herein, “opioid dependence” is generally defined as a chronicbrain disease that causes compulsive drug seeking and use.

As used herein, “alcohol dependence” is generally defined as a chronicbrain disease that causes compulsive alcohol seeking and use.

As used herein, “alcohol use disorder” is generally defined asencompassing the disorders of alcohol dependence and alcohol abuse andcan be classified as mild, moderate or severe.

As used herein, the terms “treat,” “treated,” “treating,” or “treatment”includes the diminishment or alleviation of at least one symptomassociated or caused by the state, disorder or disease being treated.

As used herein, the terms “prevent,” “preventing,” or “prevention” meansno disorder or disease development if none had occurred, or no furtherdisorder or disease development if there had already been development ofthe disorder or disease. Also considered is the ability of one toprevent some or all of the symptoms associated with the disorder ordisease.

As used herein, the terms “patient,” “individual” or “subject” refer toa human.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount,” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. An appropriate therapeutic amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of a compound of the invention wherein the compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. The phrase “pharmaceutically acceptable salt” is notlimited to a mono, or 1:1, salt. For example, “pharmaceuticallyacceptable salt” also includes bis-salts, such as a bis-hydrochloridesalt. Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe pharmaceutical compositions is contemplated. Supplementary activecompounds can also be incorporated into the compositions. Thepharmaceutical compositions can also advantageously employ a densityenhancing agent, such as a sugar, e.g., mannitol, or sorbitol and/or atonicity adjusting agent, such as sodium chloride or glycerol. Otherpharmaceutical carriers that could be used in the pharmaceuticalcompositions provided herein also include aqueous methylcellulosesolutions, fructose solution, ethanol, or oils of animal, vegetative, orsynthetic origin. The pharmaceutically acceptable carrier may alsocontain preservatives, and buffers as are known in the art.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon having thenumber of carbon atoms designated (i.e., C₁-C₄ alkyl means an alkylhaving one to four carbon atoms) and includes straight and branchedchains. Examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, and tert-butyl.

As used herein, the term “halogen” alone or as part of anothersubstituent means a fluorine, chlorine, bromine, or iodine atom,preferably, fluorine, chlorine, or bromine, more preferably, fluorine orchlorine.

Compounds of the Invention

In one embodiment, a compound of the invention has the structure ofFormula I:

or a pharmaceutically acceptable salt thereof;

wherein:

is

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound with pointsof attachment selected from the 2 and 2′ positions or the 3 and 3′positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 2 and 2′positions, then the R groups are bound at the 3 and 3′ positions; or

when the —(CH₂)_(z)C(═O)O-naltrexone moieties are bound at the 3 and 3′positions, then the R groups are bound at the 2 and 2′ positions.

In another embodiment of Formula I, both R groups are hydrogen.

In another embodiment of Formula I, both R groups are halogen.

In another embodiment of Formula I, both R groups are fluorine.

In another embodiment of Formula I, both R groups are chlorine.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula I, both R groups are methyl.

In another embodiment of Formula I, both values of z are 1.

In another embodiment of Formula I, both values of z are 2.

In another embodiment of Formula I, both values of z are 3.

In another embodiment of Formula I, both values of z are 4.

In another embodiment of Formula I, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula I, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula I, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula I, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula I, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula I, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula I, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula I, a compound of Formula Ia has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula Ia, both R groups are hydrogen.

In another embodiment of Formula Ia, both R groups are halogen.

In another embodiment of Formula Ia, both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are chlorine.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ia, both R groups are methyl.

In another embodiment of Formula Ia, both values of z are 1.

In another embodiment of Formula Ia, both values of z are 2.

In another embodiment of Formula Ia, both values of z are 3.

In another embodiment of Formula Ia, both values of z are 4.

In another embodiment of Formula Ia, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ia, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ia, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ia, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ia, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ia, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula I, a compound of Formula Ib has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula Ib, both R groups are hydrogen.

In another embodiment of Formula Ib, both R groups are halogen.

In another embodiment of Formula Ib, both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are chlorine.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ib, both R groups are methyl.

In another embodiment of Formula Ib, both values of z are 1.

In another embodiment of Formula Ib, both values of z are 2.

In another embodiment of Formula Ib, both values of z are 3.

In another embodiment of Formula Ib, both values of z are 4.

In another embodiment of Formula Ib, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ib, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ib, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ib, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ib, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ib, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula I, a compound of Formula Ic has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula Ic, both R groups are hydrogen.

In another embodiment of Formula Ic, both R groups are halogen.

In another embodiment of Formula Ic, both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are chlorine.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Ic, both R groups are methyl.

In another embodiment of Formula Ic, both values of z are 1.

In another embodiment of Formula Ic, both values of z are 2.

In another embodiment of Formula Ic, both values of z are 3.

In another embodiment of Formula Ic, both values of z are 4.

In another embodiment of Formula Ic, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Ic, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Ic, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Ic, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Ic, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Ic, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula I, a compound of Formula Id has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula Id, both R groups are hydrogen.

In another embodiment of Formula Id, both R groups are halogen.

In another embodiment of Formula Id, both R groups are fluorine.

In another embodiment of Formula Id, both R groups are chlorine.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula Id, both R groups are methyl.

In another embodiment of Formula Id, both values of z are 1.

In another embodiment of Formula Id, both values of z are 2.

In another embodiment of Formula Id, both values of z are 3.

In another embodiment of Formula Id, both values of z are 4.

In another embodiment of Formula Id, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula Id, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula Id, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula Id, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Id, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula Id, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula Id, both R groups are methyl and bothvalues of z are 4.

In another embodiment, a compound of the invention has the structure ofFormula II:

or a pharmaceutically acceptable salt thereof;

wherein:

is

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl;

both values of z, always being the same, are 1, 2, 3, or 4;

wherein the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound with points of attachment selected from the 2 and 2′positions or the 3 and 3′ positions; and

further wherein the R groups are bound with points of attachment asfollows:

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 2 and 2′ positions, then the R groups are boundat the 3 and 3′ positions; or

when the —(CH₂)_(z)C(═O)OH moiety and the —(CH₂)_(z)C(═O)O-naltrexonemoiety are bound at the 3 and 3′ positions, then the R groups are boundat the 2 and 2′ positions.

In another embodiment of Formula II, both R groups are hydrogen.

In another embodiment of Formula II, both R groups are halogen.

In another embodiment of Formula II, both R groups are fluorine.

In another embodiment of Formula II, both R groups are chlorine.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula II, both R groups are methyl.

In another embodiment of Formula II, both values of z are 1.

In another embodiment of Formula II, both values of z are 2.

In another embodiment of Formula II, both values of z are 3.

In another embodiment of Formula II, both values of z are 4.

In another embodiment of Formula II, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula II, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 1.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 2.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 3.

In another embodiment of Formula II, both R groups are hydrogen and bothvalues of z are 4.

In another embodiment of Formula II, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula II, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula II, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula II, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula II, a compound of Formula IIa has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula IIa, both R groups are hydrogen.

In another embodiment of Formula IIa, both R groups are halogen.

In another embodiment of Formula IIa, both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are chlorine.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IIa, both R groups are methyl.

In another embodiment of Formula IIa, both values of z are 1.

In another embodiment of Formula IIa, both values of z are 2.

In another embodiment of Formula IIa, both values of z are 3.

In another embodiment of Formula IIa, both values of z are 4.

In another embodiment of Formula IIa, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIa, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIa, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIa, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIa, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIa, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula II, a compound of Formula IIb has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula IIb, both R groups are hydrogen.

In another embodiment of Formula IIb, both R groups are halogen.

In another embodiment of Formula IIb, both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are chlorine.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IIb, both R groups are methyl.

In another embodiment of Formula IIb, both values of z are 1.

In another embodiment of Formula IIb, both values of z are 2.

In another embodiment of Formula IIb, both values of z are 3.

In another embodiment of Formula IIb, both values of z are 4.

In another embodiment of Formula IIb, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIb, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIb, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIb, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIb, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIb, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula II, a compound of Formula IIc has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula IIc, both R groups are hydrogen.

In another embodiment of Formula IIc, both R groups are halogen.

In another embodiment of Formula IIc, both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are chlorine.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IIc, both R groups are methyl.

In another embodiment of Formula IIc, both values of z are 1.

In another embodiment of Formula IIc, both values of z are 2.

In another embodiment of Formula IIc, both values of z are 3.

In another embodiment of Formula IIc, both values of z are 4.

In another embodiment of Formula IIc, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IIc, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IIc, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IIc, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IIc, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IIc, both R groups are methyl and bothvalues of z are 4.

In another embodiment of Formula II, a compound of Formula IId has thestructure:

or a pharmaceutically acceptable salt thereof;

wherein:

both R groups, always being the same, are selected from hydrogen,halogen, or unsubstituted C₁-C₄ alkyl; and

both values of z, always being the same, are 1, 2, 3, or 4.

In another embodiment of Formula IId, both R groups are hydrogen.

In another embodiment of Formula IId, both R groups are halogen.

In another embodiment of Formula IId, both R groups are fluorine.

In another embodiment of Formula IId, both R groups are chlorine.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl.

In another embodiment of Formula IId, both R groups are methyl.

In another embodiment of Formula IId, both values of z are 1.

In another embodiment of Formula IId, both values of z are 2.

In another embodiment of Formula IId, both values of z are 3.

In another embodiment of Formula IId, both values of z are 4.

In another embodiment of Formula IId, both values of z, always being thesame, are 1, 2 or 3.

In another embodiment of Formula IId, both values of z, always being thesame, are 1 or 2.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 1.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 2.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 3.

In another embodiment of Formula IId, both R groups are hydrogen andboth values of z are 4.

In another embodiment of Formula IId, both R groups are halogen and bothvalues of z are 1. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IId, both R groups are halogen and bothvalues of z are 2. For example, both R groups are chlorine. For example,both R groups are fluorine.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₄ alkyl and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 1.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 2.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 3.

In another embodiment of Formula IId, both R groups are unsubstitutedC₁-C₂ alkyl and both values of z are 4.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 1.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 2.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 3.

In another embodiment of Formula IId, both R groups are methyl and bothvalues of z are 4.

The compounds of Formula I are dimeric compounds, each containing twomolecules of naltrexone covalently bound to a pro-moiety. Accordingly,in another embodiment, a compound of Formula I, for example a compoundof Formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable saltthereof, is administered to a subject and metabolized in vivo to releasenaltrexone and an intermediate depicted as a compound of Formula II. Theresultant compound of Formula II, for example a compound of Formula IIa,IIb, IIc or IId, or a pharmaceutically acceptable salt thereof, may alsobe metabolized in vivo to release naltrexone. In another embodiment, acompound of Formula II, for example a compound of Formula IIa, IIb, IIcor IId, or a pharmaceutically acceptable salt thereof, is administeredto a subject and metabolized in vivo to release naltrexone.

Certain embodiments of compounds of Formula I or II are shown below inTables A and B, respectively. Compounds of Formulas I or II, orpharmaceutically acceptable salts thereof, and compounds of Tables A andB, are sometimes referred to herein as “compounds of the invention,” or“compounds provided herein.”

TABLE A Compound Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

TABLE B Compound Structure 1i 

2i 

3i 

4i 

5i 

6i 

7i 

8i 

9i 

10i

Also provided herein are pharmaceutical compositions comprising acompound of Formula I or II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. In one embodiment,the composition is administered to a subject in need of the treatment ofopioid dependence. In another embodiment, the composition isadministered to a subject in need of the treatment of alcoholdependence. In another embodiment, the composition is administered to asubject in need of the treatment of alcohol use disorder. In anotherembodiment, the composition is administered to a subject in need of theprevention of opioid dependence. In another embodiment, the compositionis administered to a subject in need of the prevention of relapse toopioid dependence. In another embodiment, the composition isadministered to a subject in need of the prevention of alcoholdependence.

In any of the compositions or methods as described herein, the compoundof Formula I or II, or a pharmaceutically acceptable salt thereof, ispresent and/or administered in a therapeutically effective amount.

In any of the compositions or methods as described herein, the compoundof Formula Ia, Ib, Ic, Id, IIa, IIb, IIc or IId, or a pharmaceuticallyacceptable salt thereof, is present and/or administered in atherapeutically effective amount.

In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is converted to one equivalent of naltrexoneand one equivalent of a compound of Formula II, upon parenteraladministration. In another embodiment, a compound of Formula I, or apharmaceutically acceptable salt thereof, is converted to up to oneequivalent of naltrexone and up to one equivalent of a compound ofFormula II, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof, isconverted to from about 0.6 to 0.95 equivalents of naltrexone and acompound of Formula II, upon parenteral administration. In anotherembodiment, a compound of Formula I, or a pharmaceutically acceptablesalt thereof, is converted to from about 0.7 to 0.95 equivalents ofnaltrexone and a compound of Formula II, upon parenteral administration.In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is converted to from about 0.8 to 0.95equivalents of naltrexone and a compound of Formula II, upon parenteraladministration. For example, about 0.7 equivalents, about 0.75equivalents, about 0.8 equivalents, about 0.85 equivalents, about 0.9equivalents, about 0.95 equivalents, or greater than 0.95 equivalents ofthe total dose of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, administered is converted to naltrexone and acompound of Formula II upon parenteral administration. In anotherembodiment, a compound of Formula I, or a pharmaceutically acceptablesalt thereof, is essentially completely converted to naltrexone and acompound of Formula II, upon parenteral administration. In anotherembodiment, the parenteral administration is via the intramuscularroute.

In another embodiment, the resultant compound of Formula II is convertedin vivo to one equivalent of naltrexone. In another embodiment, theresultant compound of Formula II is converted in vivo to up to oneequivalent of naltrexone. For example, about 0.5 equivalents, about 0.6equivalents, about 0.7 equivalents, about 0.75 equivalents, about 0.8equivalents, about 0.85 equivalents, about 0.9 equivalents, about 0.95equivalents, or greater than 0.95 equivalents of the total amount of acompound of Formula II is converted to naltrexone. In anotherembodiment, the compound of Formula II is essentially completelyconverted to naltrexone.

In another embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, may be converted in vivo to two equivalents ofnaltrexone, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof,may be converted to up to two equivalents of naltrexone, upon parenteraladministration. For example, about 1.2 equivalents, about 1.3equivalents, about 1.4 equivalents, about 1.5 equivalents, about 1.6equivalents, about 1.7 equivalents, about 1.8 equivalents, or greaterthan 1.8 equivalents of the total dose of a compound of Formula I, or apharmaceutically acceptable salt thereof, administered is converted tonaltrexone, upon parenteral administration. In another embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof, isessentially completely converted to naltrexone, upon parenteraladministration. In another embodiment, the parenteral administration isvia the intramuscular route.

In another embodiment, any one of the compounds 1 to 10 (see Table A),or a pharmaceutically acceptable salt thereof, may be converted in vivoto two equivalents of naltrexone, upon parenteral administration. Inanother embodiment, any one of the compounds 1 to 10, or apharmaceutically acceptable salt thereof, may be converted in vivo to upto two equivalents of naltrexone, upon parenteral administration. Forexample, about 1.2 equivalents, about 1.3 equivalents, about 1.4equivalents, about 1.5 equivalents, about 1.6 equivalents, about 1.7equivalents, about 1.8 equivalents, or greater than 1.8 equivalents ofthe total dose of any one of the compounds 1 to 10, or apharmaceutically acceptable salt thereof, administered is converted tonaltrexone, upon parenteral administration. In another embodiment, anyone of the compounds 1 to 10, or a pharmaceutically acceptable saltthereof, is essentially completely converted to naltrexone, uponparenteral administration. In another embodiment, the parenteraladministration is via the intramuscular route.

In another embodiment, any one of the compounds 1i to 10i (see Table B)may be converted in vivo to one equivalent of naltrexone. In anotherembodiment, any one of the compounds 1i to 10i may be converted in vivoto up to one equivalent of naltrexone. For example, about 0.7equivalents, about 0.75 equivalents, about 0.8 equivalents, about 0.85equivalents, about 0.9 equivalents, about 0.95 equivalents, or greaterthan 0.95 equivalents of the total amount of any one of the compounds 1ito 10i is converted to naltrexone. In another embodiment, any one of thecompounds 1i to 10i is essentially completely converted to naltrexone.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug or substrate tissue distribution studies.In another embodiment, substitution with heavier isotopes such asdeuterium affords greater metabolic stability (for example, increased invivo half-life or reduced dosage requirements). In another embodiment,the compounds described herein include a ²H (i.e., deuterium) isotope.Isotopically-labeled compounds are prepared by any suitable method or byprocesses using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed.

Methods of Treatment

The compounds of the invention can be used in a method of treating adisease or condition in a subject wherein treatment with a compound ofthe invention would be beneficial, said method comprising administeringto the subject a compound of the invention, or a pharmaceuticalcomposition comprising a compound of the invention.

The compounds of the invention can be used to treat a disease orcondition selected from the group consisting of opioid dependence oralcohol dependence in a subject in need thereof.

The compounds of the invention can be used to prevent a disease orcondition selected from the group consisting of opioid dependence,relapse to opioid dependence, or alcohol dependence in a subject in needthereof.

In one embodiment, the compounds of the invention can be used to treatopioid dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat alcohol dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat alcohol use disorder in a subject in need thereof.

In yet another embodiment, the compounds of the invention can be used toprevent opioid dependence in a subject in need thereof.

In yet another embodiment, the compounds of the invention can be used toprevent relapse to opioid dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used toprevent alcohol dependence in a subject in need thereof.

In another embodiment, the compounds of the invention can be used totreat addiction in a subject in need thereof. The addiction can be drugaddiction or alcohol addiction.

The drug addiction can be one or more of opioid addiction (i.e., opioiddependence) or stimulant addiction. The opioid can be one or more offentanyl, morphine, oxymorphone, buprenorphine, hydromorphone,oxycodone, hydrocodone, or the like. The drug addiction can also be oneor more of diamorphine (i.e., heroin), cocaine, nicotine, andamphetamine.

In one embodiment, compounds of the invention can be used to treat adisease or condition in a subject, wherein the subject has a toleranceto opioid medication, the subject has a history of opioid dependency orabuse, the subject is at risk of opioid dependency or abuse, or incircumstances wherein it is desirable that the risk of opioid dependenceor opioid addiction in the subject is minimized.

The compounds of the invention can also be used to treat alcoholaddiction, which can also be referred to as alcoholism. “Alcoholism”refers to an addictive disease or disorder characterized by an inabilityto control the intake of alcohol, i.e., a continued excessive orcompulsive use of alcoholic drinks. Alcoholism may involve changes anindividual's ability to metabolize alcohol as well. Diagnosis ofalcoholism can be made by psychiatric examination.

In one aspect, the compounds provided herein are useful in treatment orprevention of opioid dependence or alcohol dependence by being convertedin vivo into naltrexone, which acts as an antagonist of the μ-opioidreceptor.

In one embodiment of the methods described herein, the subject is human.

Administration/Dosage/Formulations

The compounds of the invention enable compositions with desirableproperties and advantages. For example, the compositions can beadministered once per month, or once per two months, or once per threemonths, which is particularly desirable for the subjects describedherein. Such compositions can provide many therapeutic benefits that arenot achieved with corresponding shorter acting, or immediate-releaseoral preparations of naltrexone. For example, the composition canmaintain lower, more steady plasma concentrations of naltrexone.

In one embodiment, the compound of the invention is administered in acomposition suitable for parenteral administration. In anotherembodiment, the parenteral administration is by injection. In anotherembodiment, the parenteral administration is by intramuscular injection.Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In one embodiment, a pharmaceutical composition in accordance with theinvention may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. In anotherembodiment, the material is crystalline.

In another embodiment, a pharmaceutical composition may be accomplishedby dissolving or suspending the compound of the invention in an oilvehicle.

In another embodiment, a pharmaceutical composition may be accomplishedby forming microencapsule matrices of the compound of the invention inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Injectable compositions are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

In another aspect, provided herein is a pharmaceutical compositioncomprising at least one compound of the invention, together with apharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the rate of metabolism of the particular compoundemployed, the rate of clearance of the compound, the duration of thetreatment, other drugs, compounds or materials used in combination withthe compound, the age, sex, weight, condition, general health and priormedical history of the patient being treated, and like factors wellknown in the medical arts.

A medical doctor, e.g., physician, having ordinary skill in the art mayreadily determine and prescribe the effective amount of thepharmaceutical composition required. For example, the physician couldbegin administration of the pharmaceutical composition to dose acompound of the invention at levels lower than that required in order toachieve the desired therapeutic effect and gradually increase the dosageuntil the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subjects tobe treated; each unit containing a predetermined quantity of thecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the compound and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcompounding/formulating such a compound for the treatment or preventionof opioid dependence or alcohol dependence in a subject.

In one embodiment, the compounds of the invention are formulated usingone or more pharmaceutically acceptable carriers. In one embodiment, thepharmaceutical compositions of the invention comprise a therapeuticallyeffective amount of a compound of the invention and a pharmaceuticallyacceptable carrier.

In some embodiments, a single dose of a compound of Formula I or II, ora pharmaceutically acceptable salt thereof, is from about 1 mg to about5,000 mg. In some embodiments, a single dose of a compound used incompositions described herein is less than about 2,000 mg, or less thanabout 1,800 mg, or less than about 1,600 mg, or less than about 1,400mg, or less than about 1,300 mg, or less than about 1,200 mg, or lessthan about 1,100 mg, or less than about 1,000 mg, or less than about 900mg, or less than about 800 mg, or less than about 750 mg, or less thanabout 700 mg, or less than about 600 mg, or less than about 500 mg, orless than about 300 mg or less than about 100 mg. For example, a singledose is about 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, 1,200 mg, 1,250 mg,1,300 mg, 1,350 mg, 1,400 mg, 1,450 mg, 1,500 mg, 1,550 mg, 1,600 mg,1,650 mg, 1,700 mg, 1,750 mg, 1,800 mg, 1,850 mg, 1,900 mg 1,950 mg, orabout 2,000 mg of a compound of Formula I. In a particular embodiment,the dose is administered as a single parenteral injection. In a specificembodiment, the dose is administered as a single intramuscularinjection.

For comparison purposes, VIVITROL® (naltrexone for extended-releaseinjectable suspension) is administered intramuscularly every four weeksor once a month at a dose of 380 mg naltrexone. REVIA® (naltrexonehydrochloride tablets USP) can be administered orally once per day at adose of 50 mg naltrexone hydrochloride.

In some embodiments, a single intramuscular injection is administeredwith a dose of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, of from about 500 mg to about 2,200 mg. In someembodiments, a single intramuscular injection is administered with adose of a compound of Formula I, or a pharmaceutically acceptable saltthereof, of from about 750 mg to about 2,000 mg. In some embodiments, asingle intramuscular injection is administered with a dose of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, of fromabout 1,000 mg to about 2,000 mg. In some embodiments, a singleintramuscular injection is administered with a dose of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, of from about1,200 mg to about 1,800 mg.

In another embodiment, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aduration of release of naltrexone of, from about 1 week to about 15weeks, following parenteral administration. In another embodiment, theduration of release of naltrexone is from about 2 weeks to about 15weeks, or from about 4 weeks to about 15 weeks, or from about 6 weeks toabout 15 weeks, or from about 8 weeks to about 15 weeks, or from about 8weeks to about 14 weeks, or from about 8 weeks to about 12 weeks. Inanother embodiment, the duration of release of naltrexone is about 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks. Inanother embodiment, the duration of release of naltrexone is about 8weeks. In another embodiment, the duration of release of naltrexone isabout 9 weeks. In another embodiment, the duration of release ofnaltrexone is about 10 weeks. In another embodiment, the duration ofrelease of naltrexone is about 11 weeks. In another embodiment, theduration of release of naltrexone is about 12 weeks. In anotherembodiment, the duration of release of naltrexone is about 13 weeks. Inanother embodiment, the duration of release of naltrexone is about 14weeks. In another embodiment, the duration of release of naltrexone isabout 15 weeks. In another embodiment, the duration of release ofnaltrexone is about 1 month. In another embodiment, the duration ofrelease of naltrexone is about 2 months. In another embodiment, theduration of release of naltrexone is about 3 months. In anotherembodiment, the parenteral administration is intramuscularadministration.

In another embodiment, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aminimum naltrexone blood plasma concentration of, from about 0.5 toabout 10 ng/mL, following parenteral administration. In anotherembodiment, the minimum naltrexone blood plasma concentration is atleast from about 0.7 to about 10 ng/mL, or from about 0.8 to about 8.0ng/mL, or from about 1.0 to about 8.0 ng/mL, or from about 1.0 to about6.0 ng/mL, or from about 1.5 to about 6.0 ng/mL, or from about 1.5 toabout 4.0 ng/mL, or from about 1.5 to about 3.0 ng/mL, or from about 1.5to about 2.5 ng/mL, or from about 1.5 to about 2.0 ng/mL, or from about2.0 to about 2.5 ng/mL. In another embodiment, the minimum naltrexoneblood plasma concentration is about 0.5 ng/mL, 0.8 ng/mL, 1.0 ng/mL, 1.1ng/mL, 1.2 ng/mL, 1.3 ng/mL, 1.4 ng/mL, 1.5 ng/mL, 1.6 ng/mL, 1.7 ng/mL,1.8 ng/mL, 1.9 ng/mL, 2.0 ng/mL, 2.1 ng/mL, 2.2 ng/mL, 2.3 ng/mL. 2.4ng/mL, or 2.5 ng/mL. In another embodiment, the minimum naltrexone bloodplasma concentration is about 1.0 ng/mL. In another embodiment, theminimum naltrexone blood plasma concentration is about 1.5 ng/mL. Inanother embodiment, the minimum naltrexone blood plasma concentration isabout 2.0 ng/mL. In another embodiment, the minimum naltrexone bloodplasma concentration is about 2.5 ng/mL. In another embodiment, theminimum naltrexone blood plasma concentration is about 3.0 ng/mL. Inanother embodiment, the parenteral administration is intramuscularadministration.

In other embodiments, a pharmaceutical composition comprises a compoundof Formula I or II or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; wherein the composition provides aminimum naltrexone blood plasma concentration of, from about 0.5 toabout 3.0 ng/mL, following parenteral administration, for a duration of,from about 1 week to about 15 weeks. In another embodiment, the minimumnaltrexone blood plasma concentration is at least from about 0.7 toabout 3.0 ng/mL, or from about 0.8 to about 2.5 ng/mL, or from about 1.0to about 2.5 ng/mL, or from about 1.0 to about 2.0 ng/mL, or from about1.0 to about 1.5 ng/mL, or from about 1.5 to about 2.5 ng/mL, or fromabout 1.5 to about 2.0 ng/mL, for a duration of, from about 1 week toabout 15 weeks, or from about 2 weeks to about 14 weeks, or from about 4weeks to about 14 weeks, or from about 6 weeks to about 14 weeks, orfrom about 8 weeks to about 12 weeks, or from about 10 weeks to about 12weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 1.0 ng/mL, 1.1 ng/mL, 1.2 ng/mL, 1.3 ng/mL, 1.4ng/mL, 1.5 ng/mL, 1.6 ng/mL, 1.7 ng/mL, 1.8 ng/mL, 1.9 ng/mL, 2.0 ng/mL,2.1 ng/mL, 2.2 ng/mL, 2.3 ng/mL. 2.4 ng/mL, or 2.5 ng/mL, for a durationof about 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks,or about 14 weeks. In another embodiment, the minimum naltrexone bloodplasma concentration is about 1.0 ng/mL for a duration of about 14weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 1.5 ng/mL for a duration of about 14 weeks. Inanother embodiment, the minimum naltrexone blood plasma concentration isabout 2.0 ng/mL for a duration of about 14 weeks. In another embodiment,the minimum naltrexone blood plasma concentration is about 2.0 ng/mL fora duration of about 12 weeks. In another embodiment, the minimumnaltrexone blood plasma concentration is about 2.0 ng/mL for a durationof about 10 weeks. In another embodiment, the minimum naltrexone bloodplasma concentration is about 3.0 ng/mL for a duration of about 10weeks. In another embodiment, the minimum naltrexone blood plasmaconcentration is about 3.0 ng/mL for a duration of about 8 weeks. Inanother embodiment, the parenteral administration is intramuscularadministration.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.0 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.5 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 2.0 ng/mL,following parenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.0 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 1.5 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises any one ofthe compounds 1 to 10 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier; wherein the composition providesa minimum naltrexone blood plasma concentration of about 2.0 ng/mL,following parenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.0 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.5 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 2.0 ng/mL, followingparenteral administration, for a duration of about 8 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.0 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 1.5 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

In another embodiment, a pharmaceutical composition comprises Compound 3or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein the composition provides a minimumnaltrexone blood plasma concentration of about 2.0 ng/mL, followingparenteral administration, for a duration of about 12 weeks.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,inhalation spray, sublingual or topical. The compounds for use in theinvention may be formulated for administration by any suitable route,such as for oral or parenteral, for example, transdermal, transmucosal(e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal(e.g., trans- and perivaginally), (intra)nasal and (trans)rectal,intravesical, intrapulmonary, intraduodenal, intragastrical,intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial,intravenous, intrabronchial, inhalation, and topical administration. Theterm parenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques. In one embodiment, the parenteraladministration is by injection. In another embodiment, the parenteraladministration is by intramuscular injection.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizing ordispersing agents may be used, such as a polysorbate (e.g., polysorbate20). Other formulatory agents may include preservatives and buffers asare known in the art, such as a phosphate buffer.

It is contemplated that any one of the compounds of the invention can bepresent as a co-crystal, solvate, hydrate, polymorph, or the like.Further, the compounds of the invention have a defined stereochemistryand one skilled in the art can also envision other enantiomers,diastereoisomers, or racemates of the compounds of the invention.

The present invention provides methods for the synthesis of thecompounds of each of the formulae described herein. Compounds of thepresent invention can be prepared in a variety of ways usingcommercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. The following descriptions of synthetic methodsare designed to illustrate, but not to limit, general procedures for thepreparation of compounds of the present invention.

General methods for the preparation of compounds as described herein aremodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the Formulae as providedherein. Compounds described herein are synthesized using any suitableprocedures starting from compounds that are available from commercialsources, or are prepared using procedures described herein.

The processes generally provide the desired final compound at or nearthe end of the overall process, although it may be desirable in certaininstances to further convert the compound to a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate or co-crystal thereof.

In the synthetic scheme and examples provided herein, the followingabbreviations may be used:

DMF=dimethylformamide

DMAP=4-(dimethylamino)pyridine

DIPEA (DIEA)=N,N-diisopropylethylamine

Pd(dba)₂=bis(dibenzylideneacetone)palladium(0)

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)

PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate

TBS=tert-butyldimethylsilyl

THF=tetrahydrofuran

TFA=trifluoroacetic acid

TEA=triethylamine

TMSOK=potassium trimethylsilanolate

TBME (MTBE)=tert-butyl methyl ether

T₃P=propylphosphonic anhydride

XPhos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

In one embodiment, a general method for synthesizing one or morecompounds of Formula I is provided below (Scheme 1).

As depicted for Compound 3 in Scheme 1 above, the synthesis of one ormore compounds of Formula I can be carried out, for example, by using2,5-dibromothieno[3,2-b]thiophene as a common precursor, which iscommercially available or can be readily synthesized fromthieno[3,2-b]thiophene (or the corresponding regioisomer). Pd-mediatedcross-coupling using tert-butyl((1-methoxyvinyl)oxy)dimethylsilan,followed by ester hydrolysis, yields2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetic acid. The latter can becoupled to 2 equivalents of naltrexone using standard coupling reagentssuch as (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP), propylphosphonic anhydride (T₃P), or thelike. The route can vary depending on the availability of the startingmaterial or the regiochemistry of the final target.

Examples

The invention is further illustrated by the following examples, whichshould not be construed as further limiting.

EXAMPLES Example 1: Synthesis of Compounds of the Invention 1.1 Compound1 Synthesis of dimethyl 2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetate

A mixture of 2,5-dibromothieno[2,3-b]thiophene (700 mg, 2.35 mmol),bis(dibenzylideneacetone)palladium(0) (270 mg, 0.47 mmol), zinc fluoride(730 mg, 7.05 mmol), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene(2.05 mL, 9.40 mmol) and tri-tert-butylphosphine (1 M in toluene, 0.47mL, 0.47 mmol) in anhydrous degassed dimethylformamide (14 mL) wasirradiated in the microwave at 95° C. for 1 hour 20 minutes. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas then purified by reverse phase chromatography (C18). The desiredfractions were partitioned between ethyl acetate and brine. The layerswere separated and the organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to give dimethyl2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetate (40 mg, 6% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.01 (s, 2H), 3.86 (s, 4H), 3.74 (s, 6H).

Synthesis of 2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetic Acid

To a suspension of dimethyl2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetate (85 mg, 0.30 mmol) intetrahydrofuran (3 mL), methanol (1.5 mL) and water (1.5 mL) was addedlithium hydroxide monohydrate (104 mg, 2.39 mmol). The reaction mixturewas stirred at room temperature for 1 hour. Tetrahydrofuran and methanolwere removed under reduced pressure and the mixture was then dilutedwith water and acidified with 2 M aqueous solution of hydrochloric acid.The resulting solution was extracted with ethyl acetate (2×), theorganic layers were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetic acid (90 mg, assumedquantitative yield).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetate

To a suspension of 2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetic acid(90 mg, 0.35 mmol) in anhydrous tetrahydrofuran (9 mL), was addedtriethylamine (0.2 mL, 1.41 mmol), naltrexone (264 mg, 0.77 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (438mg, 0.84 mmol). The reaction mixture was stirred at room temperature for2 hours. The reaction mixture was then diluted with ethyl acetate andwashed with saturated aqueous solution of sodium hydrogen carbonate andbrine. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was then purified byreverse phase chromatography (C18). The desired fractions werepartitioned between ethyl acetate and brine. The layers were separatedand the organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting solid was trituratedwith diethyl ether to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[2,3-b]thiophene-2,5-diyl)diacetate as a pale yellow solid(136 mg, 43% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.17 (s, 2H), 6.83 (s, 2H), 6.65 (d, 2H), 4.70(s, 2H), 4.15 (s, 4H), 3.20 (d, 2H), 3.11-2.97 (m, 4H), 2.73-2.56 (m,4H), 2.47-2.30 (m, 8H), 2.09-2.17 (m, 2H), 1.92-1.87 (m, 2H), 1.68-1.58(m, 4H), 1.26 (t, 2H), 0.88-0.86 (m, 2H), 0.56 (q, 4H), 0.15 (q, 4H).[M+H]⁺ 903.19.

1.2 Compound 2 Synthesis of dimethyl2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetate

To a suspension of bis(dibenzylideneacetone)palladium(0) (81 mg, 0.14mmol), zinc fluoride (0.83 g, 8.04 mmol) and3,4-dibromothieno[2,3-b]thiophene (0.80 mg, 2.68 mmol) inN,N-dimethylformamide (12 mL) at room temperature under an atmosphere ofnitrogen were added sequentially (1-methoxyvinyl)trimethylsilane (1.75mL, 8.04 mmol) and tri tri-tert-butyl phosphine (0.27 mL, 1 M sol, intoluene, 0.27 mmol) dropwise. The resulting reaction mixture was heatedat 100° C. under an atmosphere of nitrogen for 5 hours then was allowedto cool to room temperature. The mixture was diluted with ethylacetate(20 mL) and was washed with water (2×20 mL). The organic phase was driedover magnesium sulfate, filtered and reduced to dryness under vacuum.The crude material was purified by normal phase chromatography (50%dichloromethane in heptane) to give the desired compound dimethyl2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetate as off-white solid (0.29g, 30% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.19 (s, 2H), 3.90 (s, 4H), 3.71 (s, 6H).

Synthesis of 2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetic Acid

To a solution of dimethyl2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetate (0.23 g, 0.81 mmol) intetrahydrofuran (5 mL) was added lithium hydroxide (1.7 mL, 1 M sol. inwater, 1.7 mmol) dropwise. The resulting suspension was stirred for 18hours at room temperature then the reaction was reduced to dryness undervacuum. The crude residue was diluted with water (20 mL), and extractedwith tert-butylmethyl ether (3×20 mL). The aqueous phase was acidifiedto pH 2 using 2 M hydrochloric acid and the resulting precipitate wasextracted with ethylacetate (3×20 mL). Combined organic phases weredried over magnesium sulfate, filtered and concentrated in vacuo toafford the desired compound2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetic acid as white solid (0.20g, 96% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (br.s, 2H), 7.37 (s, 2H), 3.79 (s,4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetate

To a suspension of 2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetic acid(0.20 g, 0.78 mmol), naltrexone (0.53 g, 1.56 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(0.83 g, 1.56 mmol) in tetrahydrofuran (10 mL) at room temperature undernitrogen atmosphere was added triethylamine (0.24 mL, 1.72 mmol)dropwise over 3 min. The resulting pale yellow solution was stirred atroom temperature for 18 hours. The reaction mixture was diluted withethylacetate (30 mL), and was washed with a saturated aqueous ammoniumchloride solution (3×30 mL). Phases were separated; the aqueous phasewas re-extracted with ethyl acetate (50 mL). Combined organic phaseswere dried over magnesium sulfate, filtered and concentrated in vacuo toa white residue. The crude material was purified by reverse phasechromatography (C18, 5-95% acetonitrile in water with ammonium hydrogencarbonate at pH 9) to give the desired compoundbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetate as off-white solid (350mg. 50% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (s, 2H), 6.86 (d, 2H), 6.72 (d, 2H),5.14 (br.s, 2H), 4.97 (s, 2H), 4.29 (q, 4H), 3.18 (d, 2H), 3.07 (d, 2H),2.92 (td, 2H), 2.71-2.52 (m, 6H), 2.44-2.30 (m, 4H), 2.16-2.09 (m, 2H),1.96 (td, 2H), 1.84-1.76 (m, 2H), 1.51-1.39 (m, 2H), 1.33-1.23 (m, 2H),0.93-0.83 (m, 2H), 0.55-0.46 (m, 4H), 0.21-0.08 (m, 4H). [M+H]⁺ 903.30.

1.3 Compound 3 Synthesis of 2,5-dibromothieno[3,2-b]thiophene

To a solution of thieno[3,2-b]thiophene (10.3 g, 73.5 mmol) inchloroform (200 mL) was added N-bromosuccinimide (32.7 g, 183.8 mmol).The mixture was heated at reflux for 18 hours. The reaction mixture wasallowed to cool to room temperature before being diluted withdichloromethane (50 mL) and washed with distilled water (2×100 mL),sodium hydrogen carbonate saturated solution (100 mL), and ammoniumchloride saturated solution (100 mL) and brine (100 mL). The organiclayer was passed through a phase separator and concentrated in vacuo,yielding 2,5-dibromothieno[3,2-b]thiophene (21.8 g, 99%) as a greysolid.

¹H NMR (400 MHz, CDCl₃): δ 7.16 (s, 2H).

Synthesis of dimethyl 2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate

A two-necked flask was charged with 2,5-dibromothieno[3,2-b]thiophene(5.0 g, 16.8 mmol), zinc fluoride (5.2 g, 50.0 mmol) andbis(dibenzylideneacetone)palladium(0) (480 mg, 0.84 mmol).N,N-dimethylformamide (50 mL) was added to the flask, followed bytri-tert-butylphosphine (1.67 mL, 1.68 mmol, 1 M in toluene) andtert-butyl((1-methoxyvinyl)oxy)dimethylsilane (9.2 mL, 7.9 g, 42.0mmol). The reaction mixture was heated at 100° C. for 18 hours. Thereaction mixture was allowed to cool to room temperature. Most of thesolvent was removed in vacuo and the crude product was re-dissolved inethyl acetate (50 mL) and filtered through a Celite pad. Theconcentrated filtrate was applied directly on silica column(heptane/dichloromethane, 6:4). The appropriate fractions were combinedand concentrated in vacuo yielding dimethyl2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate as a yellow solid (2.0 gisolated). Silica column chromatography on collected mixed fractions(ethyl acetate/n-heptane, 1:4) yielded another batch of dimethyl2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate (400 mg). In total 2.4 gof dimethyl 2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate wereisolated, 52% yield.

¹H NMR (400 MHz, CDCl₃): δ 7.07 (s, 2H), 3.88 (s, 4H), 3.74 (s, 6H).

Synthesis of 2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetic Acid

To a solution of dimethyl2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate (2.0 g, 7.0 mmol) intetrahydrofuran (15 mL) and distilled water (5 mL) was added LiOH.H₂O(587 mg, 14.0 mmol). The mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with ethyl acetate (50 mL) andammonium chloride (100 mL). pH was then adjusted to pH 2 with 2 Mhydrochloric acid. The aqueous layer was further extracted with ethylacetate (3×50 mL). The combined organic layer was dried with anhydroussodium sulfate and concentrated in vacuo yielding2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetic acid as a yellow solid(1.78 g, 99%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.21 (s, 2H), 3.87 (s, 4H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetate

To a suspension of 2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetic acid(1.68 g, 6.58 mmol) in tetrahydrofuran (30 mL) was added triethylamine(1.84 mL, 13.13 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate ((benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate) (6.83 g, 13.13 mmol) and naltrexone (4.48 mg, 13.13mmol). The reaction was stirred at RT for 18 hours under an atmosphereof nitrogen. Analysis of the reaction mixture by LCMS showed ca. 70%consumption of starting material. The reaction mixture was diluted withethylacetate (100 mL) and sodium hydrogen carbonate saturated solution(100 mL). The organic layer was dried with anhydrous sodium sulfate andconcentrated in vacuo. Crude material was purified by reverse phasechromatography (C18, 30-100% acetonitrile in water with ammoniumbicarbonate buffer at pH 9). The resulting orange solid was freeze-driedfrom acetonitrile/distilled water yielding the title compound as ayellow solid (2.52 g, 42%).

¹H NMR (400 MHz, DMSO-d₆): 7.39 (s, 2H), 6.87 (d, 2H), 6.73 (d, 2H),5.15 (br s, 2H), 4.95 (s, 2H), 4.32 (s, 4H), 3.17 (d, 2H), 3.08 (d, 2H),2.92 (dt, 2H), 2.72-2.55 (m, 4H), 2.45-2.29 (m, 6H), 2.11 (d, 2H), 1.95(td, 2H), 1.80 (d, 2H), 1.46 (td, 2H), 1.33-1.23 (m, 2H), 0.88 (m, 2H),0.48 (d, 4H), 0.13 (d, 4H). [M+H]⁺ 903.33.

1.4 Compound 4 Synthesis of dimethyl2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetate

To a solution of 2,5-dibromo-3,6-dimethylthieno[3,2-b]thiophene (815 mg,2.50 mmol) in dry N,N-dimethylformamide (10 mL) under nitrogen, wasadded zinc fluoride (775 mg, 7.50 mmol),bis(dibenzylideneacetone)palladium(0) (71 mg, 0.13 mmol), a solution oftri-tert-butylphosphine in toluene (1 M, 0.25 mL, 0.25 mmol),tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (1.4 mL, 6.25 mmol). Thereaction was heated to 100° C. for 18 hours and then allowed to cool toroom temperature. The reaction was quenched by addition of water (10 mL)and was extracted with ethyl acetate (3×10 mL). The combined organicphases were dried over magnesium sulfate, filtered and concentrated todryness to give a black oil. This was purified by silica chromatography,eluted with a gradient of 5-20% ethyl acetate in heptane to givedimethyl 2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetate asa yellow solid (375 mg, 48% yield).

¹H NMR (400 MHz, CDCl₃) δ 3.78 (s, 4H), 3.70 (s, 6H), 2.24 (s, 6H).

Synthesis of give2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetic Acid

To a solution of dimethyl2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetate (361 mg,1.15 mmol) in a mixture of tetrahydrofuran:water (1:1, 20 mL) was addedlithium hydroxide monohydrate (107 mg, 2.54 mmol). The reaction wasstirred for 30 minutes at room temperature, diluted with water (20 mL)and extracted with methyl tert-butyl ether (2×10 mL). The aqueous phasewas acidified to pH 1 with hydrochloric acid 2 N (1 mL) and extractedwith ethyl acetate (3×15 mL). The combined organic phases were washedwith saturated ammonium chloride aqueous solution (10 mL), brine (10mL), dried over magnesium sulfate, filtered and concentrated to drynessto give 2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetic acidas a yellow solid (320 mg, 98%).

¹H NMR (400 MHz, DMSO-d₆) δ 3.76 (s, 4H), 2.14 (s, 6H).

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetate

To a solution of2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetic acid (320 mg,1.13 mmol) in dry tetrahydrofuran (12 mL) under nitrogen, was addednaltrexone (768 mg, 2.25 mmol), triethylamine (0.31 mL, 2.25 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(1.12 g, 2.25 mmol). The reaction was stirred overnight at roomtemperature then was concentrated to dryness, leading to a red oil. Thiswas purified by reverse phase chromatography, eluted with a gradient of0-100% acetonitrile in pH 9 ammonium bicarbonate buffer to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(3,6-dimethylthieno[3,2-b]thiophene-2,5-diyl)diacetate as a yellowsolid (593 mg, 56% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 6.81 (d, 2H), 6.68 (d, 2H), 5.10 (s, 2H),4.90 (s, 2H), 4.20 (s, 4H), 3.13 (d, 2H), 3.03 (d, 2H), 2.87 (td, 2H),2.52-2.63 (m, 4H), 2.28-2.38 (m, 4H), 2.24 (s, 6H), 2.07 (dt, 2H), 1.91(dt, 2H), 1.75 (dt, 2H), 1.40 (td, 2H), 1.25 (dd, 2H), 0.81-0.86 (m,2H), 0.42-0.47 (m, 4H), 0.07-0.01 (m, 4H). [M+2H]²⁺ 466.10.

1.5 Compound 5 Synthesis of dibutyl3,3′-(thieno[3,2-b]thiophene-2,5-diyl)(2E,2′E)-diacrylate

Into a 100 mL round-bottomed flask were added thieno[3,2-b]thiophene(700 mg, 4.99 mol), oxo(2,2,2-trifluoroacetyl)silver (4.4 g, 19.97 mol),(acetyloxy)palladio acetate (560.4 mg, 2.50 mol) and butyl prop-2-enoate(2.56 g, 19.97 mol) in propionic acid (25 mL) at room temperature. Theresulting mixture was stirred for 48 h at 50° C. under nitrogenatmosphere. The reaction was monitored by LCMS and TLC. The resultingmixture was diluted with CH₂Cl₂ (200 mL) and washed with water (3×100mL). The organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by prep-TLC (CH₂Cl₂/PE=5:1) to afford3,3′-(thieno[3,2-b]thiophene-2,5-diyl)(2E,2′E)-diacrylate (1.4 g, 60.7%)as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, 1H), 7.38 (s, 1H), 6.29 (d, 1H), 4.23(t, 2H), 1.72 (q, 2H), 1.46 (q, 2H), 0.99 (t, 3H). [M+H]⁺=393.25.

Synthesis of dibutyl 3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionate

Into a 100 mL round-bottom flask were added butyl3,3′-(thieno[3,2-b]thiophene-2,5-diyl)(2E,2′E)-diacrylate (500 mg, 1.27mmol) and cobalt chloride hexahydrate (151.5 mg, 0.64 mmol) at roomtemperature. To the above mixture was added NaBH₄ (385.5 mg, 10.19 mmol)in portions at room temperature. The resulting mixture was stirred foradditional 24 h at room temperature. The reaction was monitored by LCMS.The reaction was quenched with water/ice at room temperature. Theresulting mixture was extracted with EtOAc (3×150 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. This resulted in dibutyl3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionate (400 mg, 63.4%) as alight yellow oil. The crude product was used in the next step directlywithout further purification.

¹H NMR (400 MHz, CDCl₃) δ 6.93 (s, 1H), 4.11 (d, 2H), 3.21 (t, 2H), 2.72(t, 2H), 1.61 (d, 2H), 1.39 (d, 2H), 0.92 (d, 3H). [M+H]⁺=397.15.

Synthesis of 3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionic Acid

Into a 50 mL round-bottom flask were added butyl dibutyl3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionate (400 mg, 1.01 mmol)and NaOH (2.0 mL, 50.44 mmol) in 30 mL MeOH/THF (2:1) at roomtemperature. The resulting mixture was stirred for 4 h at roomtemperature under nitrogen atmosphere. The reaction was quenched withwater/ice at room temperature. The mixture was acidified to pH 2 withconc. HCl. The resulting mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (2×10 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The crude product was used in the next step directlywithout further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 7.11 (s, 1H), 3.07 (t, 2H),2.61 (t, 2H). [M+H]⁺=285.05.

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionate

Into a 8 mL sealed tube were added3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionic acid (400 mg, 1.41mmol), naltrexone (1.06 g, 3.09 mmol), PyBOP (1.1 g, 2.11 mmol), DMAP(34.4 mg, 0.28 mmol) and DIPEA (545.4 mg, 4.22 mmol) in DMF (25 mL) atroom temperature. The resulting mixture was stirred for overnight atroom temperature under nitrogen atmosphere. The reaction was quenched bythe addition of water (10 mL) at room temperature. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (2×10 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography (C18 using MeCN inwater, 10-100% gradient). The crude product (800 mg) was purified byprep-HPLC (C18, water/acetonitrile) to affordbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionate (139 mg, 16.5%) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (s, 2H), 6.82 (d, 2H), 6.72 (d, 2H),5.16 (s, 2H), 4.93 (s, 2H), 3.27-3.14 (m, 6H), 3.08 (d, 2H), 2.99 (t,4H), 2.92 (dd, 2H), 2.72-2.54 (m, 4H), 2.39 (t, 6H), 2.16-2.09 (m, 2H),2.00-1.91 (m, 2H), 1.80 (d, 2H), 1.47 (t, 2H), 1.30 (d, 2H), 0.96-0.83(m, 2H), 0.56-0.44 (m, 4H), 0.20-0.10 (m, 4H). [M+H]⁺=931.15.

1.6 Compound 6 Synthesis of thieno[3,2-b]thiophene-3,6-dicarbaldehyde

To a cooled (dry ice—acetone bath) solution of n-butyllithium (1.6 M inhexane, 4.7 mL, 7.5 mmol) in tetrahydrofuran (10 mL) was added dropwisea solution of 3,6-dibromothieno[3,2-b]thiophene (1.0 g, 3.35 mmol) intetrahydrofuran (8 mL) over 35 minutes under an atmosphere of argon. Themixture was stirred on the cooling bath for 2 hours. To this was addedN,N-dimethylformamide (1.3 mL) in one portion and stirring maintained onthe cooling bath for 10 minutes before allowing to room temperature for1.5 hours. The suspension was quenched with saturated aqueous solutionof sodium bicarbonate and extracted with ethyl acetate (2×) thendichloromethane [note—the aqueous layer contained lots of solid]. Theaqueous layer was filtered, washed with water and dried under vacuum togive 290 mg of thieno[3,2-b]thiophene-3,6-dicarbaldehyde. The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was triturated in aminimum amount of ethyl acetate, filtered and washed with ethyl acetateand dried under vacuum to give thieno[3,2-b]thiophene-3,6-dicarbaldehyde(253 mg, combined 83% yield).

¹H NMR (300 MHz, CDCl₃) δ 10.03 (s, 2H), 8.37 (s, 2H).

Synthesis of3,6-bis((1,3-dithian-2-ylidene)methyl)thieno[3,2-b]thiophene

To a cooled (dry ice—acetone bath) solution of2-trimethylsilyl-1,3-dithiane (1.0 mL, 5.2 mmol) in tetrahydrofuran (10mL) was added dropwise n-butyllithium (1.6 M in hexane, 3.2 mL, 5.2mmol) under an atmosphere of argon. This was allowed to 0° C. for 10minutes before cooling again (dry ice—acetone). To this was addedthieno[3,2-b]thiophene-3,6-dicarbaldehyde (250 mg, 1.3 mmol) in oneportion. The suspension was stirred rapidly on the cooling bath for 2hours before allowing warming slowly to room temperature over 2.5 hours,after which time a solution was obtained. The reaction was quenched withwater and extracted with ethyl acetate (2×) [note—the organic layercontained lots of solid]. The organic layer was filtered, washed withethyl acetate and dried under vacuum to give 168 mg of3,6-bis((1,3-dithian-2-ylidene)methyl)thieno[3,2-b]thiophene. Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was triturated in aminimum amount of dichloromethane, filtered and washed withdichloromethane and dried under vacuum to give3,6-bis((1,3-dithian-2-ylidene)methyl)thieno[3,2-b]thiophene (38 mg,combined 206 mg, 41% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.64 (s, 2H), 6.77 (s, 2H), 3.02 (t, 8H), 2.23(dt, 4H).

Synthesis of 2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetic Acid

A suspension of3,6-bis((1,3-dithian-2-ylidene)methyl)thieno[3,2-b]thiophene (168 mg,0.42 mmol) in acetic acid (8 mL) and concentrated hydrochloric acid (3.2mL) was heated at reflux (with a bleach scrubber attached to thecondenser) for 3 hours (note: suspension clears after 30 minutes but adark oily substance persists). The volatiles were removed under vacuumthen the residue was azeotroped with toluene (4×) and dried under vacuumto give 2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetic acid (114 mg,assumed quantitative yield).

¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (s, 2H), 3.67 (s, 4H). [M+H]⁺ 257.00.

Synthesis ofbis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetate

Naltrexone (296 mg, 0.87 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (491mg, 0.95 mmol) were added to a solution of2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetic acid (101 mg, 0.39 mmol)in tetrahydrofuran (14 mL) and triethylamine (0.22 mL, 1.56 mmol) andthe suspension was stirred at room temperature for 2 hours. The reactionwas quenched with saturated aqueous solution of sodium bicarbonate,extracted with dichloromethane (3×), dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica chromatography, eluted with 33% heptanes in dichloromethanecontaining 5% triethylamine. The residue was then triturated withdiethyl ether to givebis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetate (182 mg, 52% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.43 (s, 2H), 6.83 (d, 2H), 6.65 (d, 2H), 5.20(br s, 2H), 4.70 (d, 2H), 4.02 (s, 4H), 3.19 (d, 2H), 3.11-2.97 (m, 4H),2.69 (dd, 2H), 2.62 (dd, 2H), 2.47-2.30 (m, 8H), 2.13 (dt, 2H),1.91-1.85 (m, 2H), 1.60 (dt, 4H), 0.91-0.80 (m, 2H), 0.59-0.53 (m, 4H),0.17-0.12 (m, 4H). [M+2H]²⁺ 452.00.

1.7 Compound 2i Synthesis of2-(4-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[2,3-b]thiophen-3-yl)aceticAcid

To a solution of 2,2′-(thieno[2,3-b]thiophene-3,4-diyl)diacetic acid(150 mg, 0.59 mmol) in tetrahydrofuran (7.5 mL) was added naltrexone(200 mg, 0.59 mmol) and triethylamine (0.09 mL, 0.63 mmol). To thissolution was added (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (312 mg, 0.59 mmol) and the reaction was stirred atroom temperature for 18 hours. The reaction mixture was reduced todryness and the residue was purified by reverse phase chromatography(C18). The relevant fractions were collected and dried in a freeze-drierto give2-(4-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[2,3-b]thiophen-3-yl)aceticacid as a white solid (110 mg, 31%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (s, 1H), 7.40 (s, 1H), 6.87 (d, 1H),6.74 (d, 1H), 4.94 (s, 1H), 4.22 (d, 1H), 3.85 (d, 1H), 3.18 (d, 1H),3.07 (d, 1H), 2.91 (td, 1H), 2.73-2.56 (m, 3H), 2.44-2.30 (m, 4H),2.13-2.04 (m, 1H), 1.99-1.92 (m, 1H), 1.82-1.75 (m, 1H), 1.46 (td, 1H),1.32-1.23 (m, 1H), 0.92-0.83 (m, 1H), 0.55-0.44 (m, 2H), 0.14-0.08 (m,2H).

1.8 Compound 3i Synthesis of2-(5-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[3,2-b]thiophen-2-yl)aceticAcid

To a solution of 2,2′-(thieno[3,2-b]thiophene-2,5-diyl)diacetic acid(4.0 g, 15.61 mmol) in tetrahydrofuran (200 mL) was added naltrexone(5.33 g, 15.61 mmol) and triethylamine (2.18 mL, 1.58 g, 15.61 mmol). Tothe dark brown solution was added(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(8.14 g, 15.61 mmol) portion-wise over 10 minutes and the reaction leftto stir at room temperature for 18 hours. The reaction was reduced todryness to give a dark brown solid. The crude material was purified byreverse phase chromatography (5.0 g batches, water with 0.1% ammoniumformate and acetonitrile using 5-50% gradient). The correct fractionswere collected and dried in the freeze drier to give24542-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[3,2-b]thiophen-2-yl)aceticacid as a pale yellow solid (2.8 g). The solid was further purified byreverse phase chromatography. The correct fractions were collected andreduced to dryness using freeze drier to give2-(5-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[3,2-b]thiophen-2-yl)aceticacid (2.2 g, 24%).

¹H NMR (396 MHz, DMSO-d₆) δ 7.32 (s, 1H), 7.19 (s, 1H), 6.83 (d, 1H),6.69 (d, 1H), 4.91 (s, 1H), 4.26 (s, 2H), 3.83 (d, 2H), 3.14 (d, 1H),3.04 (d, 1H), 2.88 (td, 1H), 2.70-2.57 (m, 2H), 2.41-2.26 (m, 3H), 2.07(dt, 1H), 1.92 (td, 1H), 1.82-1.65 (m, 1H), 1.42 (td, 1H), 1.33-1.19 (m,1H), 0.84 (tq, 1H), 0.58-0.33 (m, 2H), 0.19-0.03 (m, 2H). [M+H]⁺ 580.20.

1.9 Compound 5i Synthesis of3-(5-(3-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-3-oxopropyl)thieno[3,2-b]thiophen-2-yl)propanoicAcid

Into a 50 mL round-bottomed flask were added naltrexone (80 mg, 0.23mmol), 3,3′-(thieno[3,2-b]thiophene-2,5-diyl)dipropionic acid (333.1 mg,1.17 mmol), EDCI (44 mg, 0.23 mmol) and DMAP (2.9 mg, 0.02 mmol) in DCM(20 mL) at room temperature. The resulting mixture was stirred forovernight at room temperature under nitrogen atmosphere. The crudeproduct (100 mg) was purified by prep-HPLC with the following conditions(water containing 0.1% formic acid with acetonitrile; 20-55% gradient)to afford3-(5-(3-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-3-oxopropyl)thieno[3,2-b]thiophen-2-yl)propanoicacid (34.5 mg, 24.2%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (s, 1H), 7.13 (s, 1H), 6.82 (d, 1H),6.73 (d, 1H), 4.93 (d, 1H), 3.26-3.15 (m, 2H), 3.08 (m, 3H), 2.95 (m,3H), 2.72-2.58 (m, 3H), 2.40 (m, 3H), 2.13 (d, 1H), 1.96 (t, 1H), 1.81(d, 1H), 1.53-1.41 (m, 1H), 1.30 (d, 1H), 0.89 (s, 1H), 0.50 (d, 2H),0.15 (d, 2H). [M+H]⁺=608.10.

1.10 Compound 6i Synthesis of2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[3,2-b]thiophen-3-yl)aceticAcid

To a solution of 2,2′-(thieno[3,2-b]thiophene-3,6-diyl)diacetic acid (50mg, 0.19 mmol) in tetrahydrofuran (2.5 mL) was added naltrexone (64 mg,0.19 mmol), triethylamine (0.02 mL, 0.19 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (100mg, 0.19 mmol). The reaction mixture was stirred at room temperature for16 hours and then concentrated under reduced pressure. The crudematerial was purified by reverse phase chromatography (C18) and freezedried to give2-(6-(2-(((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)-2-oxoethyl)thieno[3,2-b]thiophen-3-yl)aceticacid (26 mg, 23%).

¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.21 (s, 1H), 6.77 (d, 1H), 6.58(d, 1H), 4.64 (s, 1H), 3.98 (s, 2H), 3.73 (s, 2H), 3.29-3.31 (m, 1H),2.97-3.01 (m, 1H), 2.80-2.96 (m, 1H), 2.60-2.61 (m, 2H), 2.42-2.44 (m,2H), 2.10-2.23 (m, 2H), 1.86-1.89 (m, 1H), 1.49-1.55 (m, 2H), 0.90-0.91(m, 1H), 0.52-0.54 (m, 2H), 0.14-0.15 (m, 2H). [M+H]⁺ 580.00.

Example 2: Whole Blood Stability Assay

Naltrexone prodrug stability was assessed using freshly collected wholeblood (within 24-hr collection) from pooled human (n=3) donors. Theincubation mixtures were prepared by spiking the prodrugs intopre-warmed (37 degrees C.) fresh whole blood to a final concentration of50 nM. After gentle mixing, aliquots of incubation mixtures wereimmediately transferred into four different 96-deep well plates. Oneplate was used for each time point. The plates were incubated at 37degrees C. at a shaking speed of 100 rpm. At time points 15, 30, 60 and120 minutes, the reaction was quenched by addition of a mixture of waterand acetonitrile containing the internal standard (naltrexone-D₃). Timepoint 0 minutes was prepared separately by spiking the prodrugs into aquenched whole blood to obtain a final concentration of 50 nM. Allsamples were vortexed at a low speed for 15 min and centrifuged at 3900rpm for 15 min. Supernatants were transferred into 96-well plates forLC-MS/MS analysis to monitor the depletion of the prodrugs and theformation of naltrexone.

The amount of remaining prodrug and released naltrexone for each samplewas quantitated against the calibration curves prepared with the wholeblood. The human whole blood was purchased from BioreclamationIVT(Westbury, N.Y., USA). Naltrexone-D₃ was purchased from Cerilliant®(Round Rock, Tex., USA). Table C shows the half-life of the prodrugs andthe amount of naltrexone (in equivalents) measured in whole blood at the2 hour timepoint. Where multiple runs have been completed, averagevalues are reported.

TABLE C t_(1/2) at 37 degrees C. in Naltrexone formed in human wholeblood human whole blood at 2 Prodrug (min) hours (equiv.) Compound 111.0 1.70 Compound 2 15.7 1.64 Compound 3 6.46 1.48 Compound 4 20.7 1.29Compound 5 17.1 1.43 Compound 6 11.0 1.67 Reference 54.7 0.78 Compound A

Reference Compound A is disclosed in Burce et al., Journal ofChromatography, 137 (1977), 323-332 as NTX-3-terephthaloyl-NTX.

Example 3: Pharmacokinetic Evaluation of the Release of Naltrexone fromCompound 3 in Rats Following a Single Intramuscular Injection

Six male Sprague-Dawley rats were allowed to acclimate to the testfacility for at least 3 days prior to study start. For doseadministration of Compound 3, the rats were lightly anesthetized withisofluorane, the hind leg shaved and dosed intramuscularly with theformulation using a 20G needle. All animals were observed at dosing andeach scheduled collection. Serial whole blood samples were collected viasublingual route (˜150 μL) at 1, 8, and 24 hours post dose, and at 2, 4,7, 10, 15, 22, 24, 28, 35, 42, 49, 56 and 63 days post dose.

Blood samples were placed into K₂EDTA blood collection tubes. Aftercollection, blood samples were maintained chilled (on wet ice) andcentrifuged (11,500 rpm for 2 minutes at 5 degrees C.) within 30 minutesto obtain plasma. Plasma was transferred into a single vial, 1.5 mLscrew cap micro-centrifuge tube with inserts and stored at −80 degreesC. until analysis.

The formulation dosed was a crystalline suspension of Compound 3 (44.4milligrams of Compound 3 dosed per animal), wherein the crystalline testarticle was characterized with a particle size distribution ofD_(v10)=1.6 μm, D_(v50)=4.1 μm, and D_(v90)=7.7 μm (as measured vialaser diffraction). The formulation was prepared the day before dosing.Details of the formulation dosed are described in Table D below.

TABLE D Naltrexone Prodrug Dose Test Test Dose Level Conc. VolumeArticle Article (mg/kg) (mg/mL) (mL) Vehicle Storage Com- 148.07 250.00.25 0.1% polysorbate ambient pound 3 20, pH 7, 10 mM (free sodium base)phosphate buffer

Results of the above intramuscular rat study of Compound 3 are shown inTables E and F. In particular, Table E reports the average blood plasmalevels of naltrexone in rat (n=6) over 63 days following intramuscularadministration. As shown in Table E, the average blood plasma levels ofnaltrexone were near or above 1 ng/mL over the 63 day duration. Further,Table F shows the concentrations measured for parent Compound 3, and theresultant intermediate Compound 3i for each animal. As shown in Table F,the concentrations of parent Compound 3 and the resultant intermediatewere generally low to not measurable (below the limit of quantitationreported below). These data show efficient conversion of Compound 3 inrats to naltrexone over 63 days with minimal observed plasmaconcentrations of the intact prodrug (i.e., Compound 3) or its resultantintermediate (i.e., Compound 3i).

TABLE E NTX conc. Standard Days (ng/mL) Deviation 0.042 (1 hour) 7.430.87 0.33 (8 hour) 6.41 0.74  1 6.41 1.13  2 6.40 1.24  4 13.0 4.99  719.9 10.9 10 15.2 8.42 15 7.52 4.51 22 4.01 1.85 24 4.15 2.20 28 3.512.28 35 3.03 2.19 42 2.44 1.61 49 1.98 1.89 56 0.67 0.69 63 1.67 0.80

TABLE F Compound 3 conc. (ng/mL)* Compound 3i conc. (ng/mL)* Days Rat 1Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6  0.042<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 (1 hr)  0.33<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 (8 hr)  1<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2  2 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2  4 <0.1 <0.1 <0.1 <0.1<0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2  7 <0.1 <0.1 <0.1 <0.1 <0.10.161 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 10 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1<0.2 <0.2 <0.2 <0.2 <0.2 <0.2 15 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2<0.2 <0.2 <0.2 <0.2 22 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2<0.2 <0.2 24 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.228 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 35 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 42 <0.1 <0.1 <0.10.128 <0.1 <0.1 0.805 0.149 <0.2 <0.2 <0.2 <0.2 49 0.134 0.131 0.138<0.1 0.143 <0.1 0.423 <0.2 <0.2 <0.2 <0.2 <0.2 56 2.02 0.753 0.501 0.2810.245 0.237 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 63 0.184 0.229 0.223 0.2340.255 0.207 <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 *Values with a “<” signindicate concentrations below the limit of quantitation

Example 4: Characterization and Crystallization Method for Compound 3

Compound 3 was crystallized according to the following procedure. 86.1mL of dimethylacetamide was added to 11.229 grams of Compound 3. Themixture was stirred, sonicated, and mixed with a homogenizer to form amilky suspension at room temperature. The mixture was stirred on a hotplate set to 50 degrees C. until a hazy brown solution was achieved. Thehazy solution was polish filtered (glass fiber 1 micron pore size, 25 mmsyringe filter (2 filters used)) while still warm into a 500 mL flask. Aclear brown solution resulted. An equal volume of isopropanol (86 mL)was added at room temperature as a single aliquot with stirring. Acloudy precipitate was observed at the interface of the solvent andantisolvent that immediately cleared. Solution was still clear afterantisolvent addition. Solution began to become cloudy within 5 minutesof antisolvent addition and slowly became more cloudy over time. After1.3 hours, a second volume of isopropanol (86 mL) was added at roomtemperature as a single aliquot with stirring. After 1 hour, a thirdvolume of isopropanol (86 mL) was added at room temperature as a singlealiquot with stirring. A temperature probe was added to the slurry andthe temperature on the stir plate was set to 40 degrees C. After 20minutes, the heat was turned off. After cooling to room temperature, thesample was vacuum filtered using a polypropylene filter funnel with 10micron polyethylene fritted disk. The resultant filter cake was washedwith room temperature isopropanol (approximately 300 mL) resulting in amother liquor that was slightly hazy. The filter cake was broken up witha spatula and the entire filter was placed in a vacuum oven to dryovernight at 40 degrees C. with a nitrogen bleed. The material was driedovernight.

FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of thecrystalline form. The PXRD pattern was collected using a Rigaku MiniflexII Desktop X-ray diffractometer, with CuKα radiation at 15 mA and 30 kV.Each sample was mounted on a zero background sample holder. A scan speedof 7.5°/min 2-theta was chosen, coupled with a sampling width of 0.2°2-theta and a start and stop angle of 2 degrees and 40 degrees 2-theta.The crystalline form of Compound 3 can also be characterized by any one,any two, any three, any four, any five, or any six or more of the peaksin the PXRD diffractogram in FIG. 1 including, but not limited to, 7.4511.24, 12.05, 12.98, 14.98, 16.06, 17.18, 18.41, 18.93, 20.31, 20.49,21.96 and 22.70 degrees 2-theta (±0.2 degrees).

For example, in one embodiment, the crystalline form of Compound 3 canbe characterized by the PXRD peaks at 7.45, 11.24, 12.98, and 16.06degrees 2-theta (±0.2 degrees). In another embodiment, the crystallineform of Compound 3 can be characterized by the PXRD peaks at 12.05,14.98, 17.18 and 18.93 degrees 2-theta (±0.2 degrees). In anotherembodiment, the crystalline form of Compound 3 can be characterized bythe PXRD peaks at 7.45, 12.05, 14.98 and 16.06 degrees 2-theta (±0.2degrees).

Differential scanning calorimetry (DSC) was also performed on thecrystalline form of Compound 3. An endotherm was measured with an onsettemperature at 194.5 degrees C. and a melt temperature at 196.9 degreesC. The DSC thermogram was measured with a TA Instruments Q2000 DSC. Anapproximately 3-6 mg sample was accurately weighed into a hermetic pan.Dry nitrogen was used as a purge gas (50 mL/min nitrogen) and a heatingrate of 1 or 5 degrees C. min⁻¹ up to 300 degrees C. was applied.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-21. (canceled)
 22. A compound of Formula Ic:

or a pharmaceutically acceptable salt thereof; wherein: both R groups,always being the same, are selected from hydrogen, halogen, orunsubstituted C₁-C₄ alkyl; and both values of z, always being the same,are 1, 2, 3, or
 4. 23. The compound of claim 22, wherein both R groupsare hydrogen.
 24. The compound of claim 22, wherein both R groups arehalogen.
 25. The compound of claim 22, wherein both R groups areunsubstituted C₁-C₄ alkyl.
 26. The compound of claim 22, wherein both Rgroups are methyl.
 27. The compound of claim 22, wherein both values ofz are
 1. 28. The compound of claim 22, wherein both values of z are 2.29-35. (canceled)
 36. A compound of claim 22 selected from the groupconsisting of:

and a pharmaceutically acceptable salt thereof. 37-72. (canceled)
 73. Apharmaceutical composition comprising a compound of claim 22 and apharmaceutically acceptable carrier.
 74. The pharmaceutical compositionof claim 73, wherein the composition is adapted for parenteraladministration.
 75. The pharmaceutical composition of claim 74, whereinthe composition provides a duration of release of naltrexone of about 9weeks following parenteral administration.
 76. The pharmaceuticalcomposition of claim 74, wherein the composition provides a duration ofrelease of naltrexone of about 13 weeks following parenteraladministration.
 77. The pharmaceutical composition of claim 74, whereinthe parenteral administration is an intramuscular injection.
 78. Amethod of treating opioid dependence in a subject in need thereof,comprising administering to the subject a compound of claim
 22. 79. Amethod of treating alcohol dependence in a subject in need thereof,comprising administering to the subject a compound of claim
 22. 80. Amethod of preventing relapse to opioid dependence in a subject in needthereof, comprising administering to the subject a compound of claim 22.81. A method of treating alcohol use disorder in a subject in needthereof, comprising administering to the subject a compound of claim 22.82-89. (canceled)